rs565781501

chr12-32747364-C-CT

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_001040436.3(YARS2):c.1275-2_1275-1insA variant causes a splice acceptor change. The variant allele was found at a frequency of 0.000602 in 1,613,674 control chromosomes in the GnomAD database, including 6 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0033 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (2 hom.)
• Consequence: YARS2 NM_001040436.3 splice_acceptor
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.11

Genes affected

YARS2 (HGNC:24249): (tyrosyl-tRNA synthetase 2) This gene encodes a mitochondrial protein that catalyzes the attachment of tyrosine to tRNA(Tyr). Mutations in this gene are associated with myopathy with lactic acidosis and sideroblastic anemia type 2 (MLASA2). [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• BP6: Variant 12-32747364-C-CT is Benign according to our data. Variant chr12-32747364-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 215425.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00325 (495/152286) while in subpopulation AFR AF= 0.0111 (461/41558). AF 95% confidence interval is 0.0103. There are 4 homozygotes in gnomad4. There are 234 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YARS2	NM_001040436.3	c.1275-2_1275-1insA		splice_acceptor_variant		ENST00000324868.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YARS2	ENST00000324868.13	c.1275-2_1275-1insA		splice_acceptor_variant		1	NM_001040436.3	P1
YARS2	ENST00000548490.1	c.*286-2_*286-1insA		splice_acceptor_variant, NMD_transcript_variant		5
YARS2	ENST00000551673.5	n.172-2_172-1insA		splice_acceptor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 497 AN: 152168 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000942 AC: 235 AN: 249590 Hom.: 1 AF XY: 0.000725 AC XY: 98 AN XY: 135126

Gnomad AFR exome AF: 0.0123

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000326 AC: 477 AN: 1461388 Hom.: 2 Cov.: 31 AF XY: 0.000309 AC XY: 225 AN XY: 727014

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152286 Hom.: 4 Cov.: 32 AF XY: 0.00314 AC XY: 234 AN XY: 74466

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00212 Hom.: 1

Bravo AF: 0.00352

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 11, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs565781501; hg19: chr12-32900298;